A variety of quaternary ammonium salts are pharmaceutically active.
Bretylium tosylate 1 (also known as 2-bromobenzylethyldimethylammonium p-toluenesulfonate) has the structure: 
It is a known Class III antiarrhythmic agent and an adrenergic blocking agent. The bretylium cation of this compound is reported to directly modify the electrical properties of the myocardium. It also is reported to depress adrenergic neural transmission by blocking neuronal norepinephrine release and re-uptake. Bretylium tosylate consequently has been used worldwide to suppress life-threatening ventricular tachyarrhythmias, such as ventricular tachycardia and fibrillation. Bacaner (in U.S. Reissue Pat. No. 29,618, incorporated herein by reference) discloses suppressing cardiac ventricular fibrillation and cardiac arrhythmias generally by administering bretylium tosylate. Similarly, Bacaner (in U.S. Pat. No. 3,911,125, incorporated herein by reference) discloses treating angina pectoris, treating coronary insufficiency, and preventing myocardial infarction by administering bretylium tosylate and bethanidine sulfate.
Bretylium is the only known drug that can induce the phenomenon of spontaneous defibrillation in large hearts (dog and man). In dogs treated with bretylium, electrically induced ventricular fibrillation by superthreshold shocks persisting for as long as two minutes is often not sustained because spontaneous defibrillation to sinus rhythm occurs repeatedly. Non-sustained ventricular fibrillation has also been observed in bretylium-treated dogs and humans subjected to coronary artery legation. This phenomenon has also been reported in patients receiving bretylium treatment.
Unformulated bretylium tosylate exhibits poor and unpredictable absorption into the bloodstream when orally ingested. Thus, oral administration of bretylium tosylate alone is generally unsuitable for treating heart conditions and has not been approved by the FDA because of poor and unpredictable tablet absorption. Accordingly, bretylium tosylate is instead usually administered parenterally in the form of an injectable solution. This mode of administration, however, is inconvenient and painful, particularly for chronic administration, and slow in onset of therapeutic action because bretylium tosylate has poor lipid solubility and difficulty crossing capillary and heart membranes.
Administration of bretylium tosylate (or other quaternary ammonium compounds) may also result in severely reduced ambulation in a recipient due to a sharp drop in blood pressure on assuming the upright position, resulting in dizziness and loss of consciousness. The severity of this side-effect, however, can be reduced (and the therapeutic effects of the bretylium cation can be enhanced) by administering a tricyclic anti-depressant agent (e.g., protriptyline, mazindol, amitriptyline, nortriptyline, or desipramine) with the bretylium tosylate, as disclosed by Bacaner in U.S. Pat. No. 5,036,106.
A number of studies on the bioavailability of bretylium tosylate have been described in the literature. Most of these studies, however, have primarily focused on parenteral, rectal, and other non-ingested compositions comprising bretylium tosylate. Most also involve the administration of bretylium tosylate compositions under alkaline conditions.
Neubert et al. (in Ion Pair Approach of Bretylium, Pharm. Ind. 54, Nr. 4 (1992)) disclose a series of experiments in which bretylium tosylate was studied in the presence of saccharin, dodecylsulfate, or hexylsalicylate anions. The partition coefficient for the bretylium ion in the presence of these anions was measured using an alkaline (pH=7.2) n-octanol/buffer system and using an alkaline (pH=7.2) absorption model system employing an artificial lipid membrane. Bretylium absorption in vivo was also measured in rabbits receiving the bretylium tosylate in combination with these anions by i.v. injection (an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2)) or rectal administration.
Neubert et al. (in Influence of Lipophilic Counter Ions on the Transport of Ionizable Hydrophilic Drugs, J. Pharm. Pharmacol. 1991, 43: 204-206) disclose a series of experiments on the influence of the counterions hydroxynaphthoate, naphthylsulphonate, adamantoate, desoxycholate, dehydrocholate, octanoate, decanoate, dodecanoate, hexadecanoate, and hexylsalicylate on the transport of bretylium using an alkaline (pH=7.2) absorption model system. It was reported that the use of hydroxynaphthoate, adamantoate, desoxycholate, or dehydrocholate counterions resulted in minimal or no increase in bretylium transport across the membrane. No therapeutic or electrophysiologic action is disclosed.
Neubert et al. (in Drug Permeation Through Artificial Lipoid Membranes, Pharmazie 42 (1987), H. 5) evaluated the effect of alkylated derivatives of salicylic acid, particularly hexylsalicylic acid, on the partition and transport of ionized basic drugs including bretylium tosylate using lipophilic membranes in alkaline (pH=7.2) lipoid membrane models.
Hartl et al. (in Influence of the Ion-Pair-Formation of Bretylium and Hexylsalicylic Acid on Their Influence on Blood Plasma Levels in Dogs, Pharmazie 45 (1990), H. 4) report an improvement in biological bretylium levels in dog plasma when a bretylium-tosylate/hexylsalicylic acid combination was administered to dogs by i.v. injection (an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2)). Hartl et al., however, do not discuss how to improve the bretylium level in the myocardium of the heart or the therapeutic effects of doing so or inducing sympathetic blockade.
Neubert et al. (in Influence of the Ion-Pair-Formation on the Pharmacokinetic Properties of Drugs (Part 4), Pharmazie 43 (1988), H. 12) report a series of experiments to determine the pharmacokinetic parameters of bretylium tosylate administered in combination with hexylsalicylic acid in rabbits by i.v. injection or rectally. No therapeutic or electrophysiologic action is disclosed, nor is there any reference to oral administration.
Amlacher et al. (in Influence of Ion-Pair Formation on the Pharmacokinetic Properties of Drugs, J. Pharm. Pharmacol. 1991, 43: 794-797) disclose a series of experiments to measure the partition coefficients for the bretylium ion in the presence of salicylic acid using an alkaline (pH=7.2) n-octanol/buffer system. Bretylium absorption in vivo was also measured in rabbits receiving an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2).
Neubert et al. (in Influence of the Ion-Pair-Formation on the Pharmacokinetic Properties of Drugs (Part 5), Pharmazie 44 (1989), H. 9) disclose a series of experiments on the effect of ion-pair formation on the elimination of bretylium and hexylsalicylic acid in rats. In these experiments, the rats received an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2) and, in some instances, an oral dose of cholestyramine. Neubert et al. concluded that the pharmacokinetic parameters of bretylium were not influenced by hexylsalicylic acid.
Cho (in WO 87/05505) discloses compositions comprising particles consisting essentially of a solid emulsifying agent and a surfactant, a biologically active proteinaceous material bound to the surface of the particles, and a lipid coating surrounding such particles. While Cho is primarily directed to pharmaceutical compositions comprising insulin, he does state generally that other pharmaceutical agents, such as bretylium tosylate, could be employed. Additional ingredients in the composition are described to include, among others, sodium lauryl sulfate (as a surfactant), sodium bicarbonate, and citric acid.
Stanley et al. (in U.S. Pat. Nos. 5,288,497 and 5,288,498) disclose a dissolvable or non-dissolvable drug containing matrix form for administering a drug for absorption through the mucosal tissues of the mouth, pharynx, and esophagus. Stanley et al. identify a large group of active drugs that can be administered buccally in accordance with the invention. These references further disclose a variety of additional ingredients that can be included in the matrix including, among others, sodium lauryl sulfate and sodium dodecyl sulfate (as “permeation enhancers”) and buffering systems (to adjust salival pH). Although the Stanley references list bretylium tosylate as one of the drugs that can be administered in this manner, bretylium tosylate is very bitter and too unpalatable for human consumption by this mode of administration.
Finally, Bacaner et al. (in “Synergistic Action of Bretylium With Low Doses Of Propranolol Renders The Canine Heart Virtually Invulnerable To Sustained Ventricular Fibrillation”, Circulation, Supp. IV, page 111 (1987)) disclose a synergistic enhancement in the onset and magnitude of the anti-fibrillatory action caused by bretylium tosylate when a small, non-β-blocking dosage of propranolol is added to a bretylium tosylate bolus injected into dogs. This synergism also has been demonstrated with other β-blocking drugs (sotalol, esmolol, metoprolol and carvedilol).